Long known to be critical for innate immunity, the role of Cr1 and 2 in the adaptive immune response was solidified by experiments using Cr2-/- mice (which lack both receptors as they are encoded at a single locus, Cr2.) These mice showed a profound defect in response to T-dependent foreign Ag. Recent insight gained from these mice suggests that the regulation of self-reactive B cells in these mice is also perturbed. Specifically, mice lacking CRsl/2 fail to maintain tolerance to a model self-Ag, HEL (the HEL/anti-HEL Tg mouse model permits the study of B cells that are functionally inactive or anergic). In addition, breeding these animals to B6/lpr accelerated their progression to SLE-like disease. C4 null mice showed a similar phenotype as the Cr2-/-, suggesting an explanation to the long-standing paradox that C4 deficiency predisposes to SLE (in humans): normally targeting of ubiquitous complement-coated self-Ags to CRexpressing resident FDCs permits deletion or functional inactivation of self-reactive B cells. To test this hypothesis, I propose to: 1) Determine which cell type must express CR1 for the maintenance of tolerance; 2) Determine whether the co-receptor signaling capability of CR1 is necessary for the same, and; 3) Test whether developing B cells are anergized in the BM after targeting of self Ags to this tissue.